The survival outcomes of localized low‐risk prostate cancer, a population‐based study using NCDB

Abstract Background The optimal treatment approach for low‐risk prostate cancer (LRPC) remains controversial. While active surveillance is an increasingly popular option, definitive local treatments, including radical prostatectomy (RP), external beam radiotherapy (EBRT), and prostate seed implantation (PSI), are also commonly used. This study aimed to evaluate the survival outcomes of patients with LRPC using a large patient population from the National Cancer Database (NCDB). Methods We analyzed data from 195,452 patients diagnosed with LRPC between 2004 and 2015 using the NCDB. Patients were classified based on their treatment modalities, including RP, EBRT, PSI, or no local treatment (NLT). Only patients with Charlson–Deyo comorbidity scores of 0 or 1 were included to ensure comparability. Propensity score analysis was used to balance the treatment groups, and the accelerated failure time model was used to analyze the survival rates of the treatment groups. Results After a median follow‐up of 70.8 months, 24,545 deaths occurred, resulting in an all‐cause mortality rate of 13%. RP demonstrated a survival benefit compared with NLT, particularly in patients younger than 74 years of age. In contrast, radiation treatments (EBRT and PSI) did not improve survival in the younger age groups, except for patients older than 70 years for EBRT and older than 65 years for PSI. Notably, EBRT in patients younger than 65 years was associated with inferior outcomes. Conclusion This study highlights the differences in survival outcomes among LRPC treatment modalities. RP was associated with improved survival compared to NLT, especially in younger patients. In contrast, EBRT and PSI showed survival benefits primarily in the older age groups. NLT is a reasonable choice, particularly in younger patients when RP is not chosen. These findings emphasize the importance of individualized treatment decisions for LRPC management.

Patients diagnosed with localized, low-risk prostate cancer (LRPC) 1,2 face intricate treatment choices, ranging from active surveillance (AS) to definitive local interventions, including radical prostatectomy (RP), external-beam radiation therapy (EBRT), or prostate seed implantation (PSI).The selection of the most suitable approach is influenced by various factors, including age, comorbidities, and preferences of both physicians and patients.
In recent years, AS has gained widespread acceptance as a management option for LRPC that transcends demographic boundaries. 3,4Studies have demonstrated its safety and feasibility over a 5-10-year period, [5][6][7][8] making it the preferred initial management strategy for LRPC. 2 However, it is essential to note that AS itself does not improve the oncologic outcomes.The long-term trajectory of AS remains somewhat uncertain, except in cases of very LRPCs. 9For example, Klotz et al. reported that the 10and 15-year cause-specific survival rates in a single-arm prospective AS cohort were 98.1% and 94.3%, respectively.Nevertheless, approximately one-third of the patients initially managed with AS eventually required definitive local treatment. 81][12] Notably, an increasing number of patients who started observation eventually received local therapies, RP, or radiotherapy over time: 20% within 10 years in the PIVOT trial, 11 55% in 10 years, and 61% by 15 years in the ProtecT trial. 12Despite these advancements, optimal management of localized LRPC remains a contentious issue.Prospective studies, including the ProtecT trial, often face limitations due to the relatively small sample sizes in each cohort for practical reasons, necessitating extended follow-up periods spanning decades to discern outcomes.
To address these challenges, we harnessed the extensive patient data from the National Cancer Database (NCDB).Our analysis focused on patients diagnosed with LRPC between 2004 and 2015, with inclusion criteria limited to individuals with Charlson-Deyo comorbidity scores (C/DCS) of 0 or 1 to minimize the potential biases related to comorbidities.Our goal was to enhance our understanding of the overall survival (OS) outcomes associated with various LRPC treatments, thereby assisting in optimizing management strategies.

| Patient selection
This retrospective study utilized NCDB data, a comprehensive hospital-based clinical oncology database supported by the American College of Surgeons' Commission on Cancer (CoC) and the American Cancer Society.The NCDB collects data from over 1500 CoCaccredited hospitals and covers approximately 70% of newly diagnosed cancer cases in the United States.We focused on patients diagnosed with LRPC between 2004 and 2015, as defined by the D'Amico and NCCN criteria (PSA <10 ng/mL, cT1-cT2a, and GS ≤6). 1,2Patients who did not meet the criteria for LRPC, those with missing clinical staging data, or those with missing survival data were excluded.In NCDB, comorbidities were recorded based on the Charlson-Deyo comorbidity score (C/ DCS). 13Only patients with a C/DCS score of 0 or 1 were included to maintain cohort comparability.The CONSORT diagram in Figure 1 visually represents the study exclusion criteria, defining the final cohort with 195,452 eligible patients.

| Ethical considerations
No institutional review board approval was required given the use of de-identified NCDB data, which complies with strict data confidentiality and HIPPA privacy regulations.

K E Y W O R D S
active surveillance, external beam radiation, low-risk prostate cancer, prostate seed implantation, prostatectomy

| Treatment
The primary independent variable of interest was treatment modality: RP, EBRT, PSI, or no local treatment (NLT).Patients who received systemic therapy or other treatment were excluded from the study.Differentiating between AS and other reasons for refusing local treatment was impossible because of NCDB limitations.

| Statistical methods
Chi-square tests were conducted for categorical variables to compare confounder differences among treatment groups, presented as frequency (percentage).Propensity score analysis was employed to address the treatment selection bias resulting from a lack of randomization. 14Propensity scores were calculated using multinomial logistic regression based on demographic variables (age, race, insurance status, income, educational level, area, facility type, and race-facility type interaction).Inverse probability of treatment weight (IPTW) was applied to balance treatment groups. 15A chisquared test with IPTW as the weight was conducted to validate the balance of the treatment groups.
The primary outcome measure was OS.Kaplan-Meier survival plots stratified by treatment groups were compared using the log-rank test, and pairwise comparisons were used to determine the significance between treatments.
][18][19] Because estimating the AFT model's parameters requires assuming a time distribution, the Weibull distribution was chosen as it resulted in the smallest Akaike information criterion and Bayesian information criterion.The AFT models for the treatment groups were stratified by age and other demographics, with all tests adjusted using IPTW.
Statistical analyses were performed using SAS Enterprise Guide 9.4 HF3 with a significance level of α = 0.05.

| Patient characteristics
We identified 195,452 LRPC patients in the NCDB database between 2004 and 2015 (Table 1).Most (74%) were under 70 years old, 29% were under 60, and only 10% were aged 75 years or older.The majority were Caucasian (85%), followed by African American (13%) and other races (1.8%).Most LRPC patients (79%) received care in academic programs or comprehensive community cancer programs.Most patients were covered by private (51%) or governmental (46%) insurance, with uninsured patients comprising only 1.3% of the population.
In patients receiving local therapies, 99.6% of RP, 99.1% of EBRT, and 99.9% of PSI treatments occurred within the first year of diagnosis, indicating primary rather than deferred therapies.
Table 2 displays patient demographics by treatment modalities, revealing significant differences in age, race, insurance type, income, education, residence, and treatment facility among the NLT, RP, EBRT, and PSI groups.Propensity score analysis was conducted to balance the treatment groups using multinomial logistic regression and IPTW.This achieved group comparability, with no statistically significant differences (p > 0.05) in patient demographics between the treatment groups.(Table 2).All further analyses were performed using IPTW-corrected data.

| Survival outcomes
During a median follow-up of 70.8 months, 24,545 deaths occurred, resulting in an all-cause mortality rate of 13%. Figure 2 presents the Kaplan-Meier plot depicting OS probabilities following IPTW adjustment for different management modalities.In the initial 50 months, the survival probabilities for the four treatment modalities overlapped, signifying comparable survival among the NLT, surgery, and radiation options.Significant differences in survival rates emerged after 75 months, with RP consistently maintaining the highest survival rate, whereas NLT exhibited the lowest survival rate among the treatment groups beyond 75 months (Figure 2 and Table S2).The Kaplan-Meier plot without IPTW adjustment is shown in Figure S1.Log-rank test significant differences in survival probabilities between treatments (Table S3).Survival probabilities estimated by AFT model differed significantly among the treatment groups (p < 0.0001) with the odds ratios of 1.21, 1.05, and 1.13 for RP, EBRT, and PSI, respectively, compared to NLT (Table 3), indicating improvement of survival for RP, EBRT, and PSI over NLT.

| Survival by age groups
Along with comorbidities, age significantly influences treatment decisions in clinical practice.no insurance, potentially reflecting the patient population with Medicare coverage, that is, older age groups, aligning with the data shown in Table 4.

| Survival by income and education
RP improved survival regardless of income and education level, whereas EBRT and PSI primarily benefited lowerincome patients and potentially older individuals.Both EBRT and PSI were advantageous at varying educational levels, except for those with lower education levels (<7%), suggesting a potential disparity (Table S4).

| Survival by location and facility
EBRT benefited patients in metropolitan areas, whereas PSI showed survival benefits across all locations, suggesting the role of treatment logistics in radiation techniques.Treatment benefits varied among the different facilities for both EBRT and PSI (Table S4).

| DISCUSSION
In this population-based retrospective study of LRPC, we analyzed various treatment outcomes using NCDB data, encompassing nearly 200,000 patients, which is the largest LRPC-focused study to date.Our findings revealed distinct survival outcomes among different treatment modalities.RP exhibited lower all-cause mortality, a benefit observed across demographics up to the age of 74 years, but diminishes with age.The survival of patients with NLT was comparable to that of patients with EBRT and PSI, except for older patients.EBRT and PSI confer survival benefits mainly for those over 65 years (PSI) and 70 years (EBRT).
The survival benefit of RP has been established historically, 10,[20][21][22] primarily for intermediate-risk prostate cancer.However, this study, for the first time, unveiled the advantage of RP in LRPC owing to its substantial sample size of 50,000 patients per group.It addresses the limitation of small sample sizes in prospective studies and enhances the statistical power for treatment difference detection.
The long-term survival advantage of RP over NLT in LRPC is conceivable because NLT alone lacks a direct impact on survival.Despite its low-risk nature, LRPC can progress and develop metastasis over time.An extended follow-up study revealed a 15-year prostate cancer-specific mortality rate of 5.7% for AS. 8 Without deferred local intervention, mortality could increase to 11% (15 years) and 25% (20 years), respectively. 23It is worth noting that most patients in this study received primary local treatment within the first year of diagnosis.Only a tiny fraction of patients (<0.4% for RP, <0.9% for EBRT, <0.1% for PSI) received local treatment longer than a year later from the time of diagnosis.In a recent Cochrane systematic review, 24 RP was found to improve oncologic outcomes compared to watchful waiting (WW) and probably reduced the risks of disease progression and metastatic disease, but similar survival outcomes, with limited 10-year follow-up, compared to AS.
This study found that RP outperformed EBRT and PSI in terms of LRPC survival.We hypothesized that radiation may not fully eradicate prostate tissue, potentially leaving behind surviving tissue that fosters synchronous cancer development due to multifocality and field cancerization from ongoing environmental carcinogen exposure or genetic predisposition.Prostate cancer stem cells may also contribute to therapy resistance. 25Therefore, the therapeutic effects of radiation may not be durable, which could explain the negative impact of EBRT on survival in younger patients.The ability of RP to eradicate prostate tissue and cancer stem cells reduces the risk of synchronous or secondary prostate cancer.Furthermore, because of the inherent risk of sampling bias with prostate biopsy, higher-risk prostate cancer with occult, synchronous, or metachronous high-grade disease missed by biopsy could be included in the radiation groups.
The benefit of RP was shown across racial groups between black and white, insurance types, income levels, neighborhoods of various education levels, regions of living across metro, urban, and rural, and facility types, except for those of other races, uninsured, and of the unknown area of living.This latter population also did not benefit from EBRT and PSI, likely reflecting disparities and potentially increased confounding risks associated with underlying social and economic factors.Radiation seemed beneficial across race and education levels, particularly to those with government insurance and with relatively lower incomes, consistent with the observation from the age-controlled analysis (Table 4) that radiation benefits more to those of older age groups, typically the Medicare population.In addition, the difference of treatment logistics between EBRT and PSI, accessibility to facilities, and social support, including transportation, could also impact the choices and benefits of radiation (Table S4).
In recent years, the management of LRPC has undergone a significant paradigm shift, with AS rapidly becoming the dominant choice since 2010 3 because of societal recommendations.Current guidelines from AUA/ASTRO/ SUO and NCCN endorse AS as a safe approach for LRPC, especially in patients with very low-risk prostate cancer. 2,26hile AS may not directly improve oncologic outcomes in LRPC, it offers the advantage of preserving the quality of life by avoiding treatment-related side effects.This is particularly important, given the lack of a universally recognized optimal treatment for LRPC.Our study highlights that apart from RP, NLT demonstrated non-inferior survival outcomes to EBRT or PSI in younger age groups.Thus, if RP is not the course of action chosen by patients and providers, NLT represents a reasonable alternative for individuals under the age of 65.
The findings of this study are hypothesis-generating.The multifocal, heterogeneous, and dynamic nature of prostate cancer with potential low-to high-grade progression 27,28 creates uncertainties in clinical management.The clinical criteria we base our treatment decisions upon may be inadequate and imprecise. 29To address these concerns, the National Institute for Health and Clinical Excellence recommends the use of multiparametric MRI as a prerequisite for AS.Additionally, repeat prostatic biopsy during AS aids in tracking disease progression and changes over time.The current AUA/ASTRO/SUO guidelines advocate RP or radiotherapy as suitable for LRPC patients with risk factors, including perineural invasion, African American race, family history, or genetic predisposition to lethal or metastatic prostate cancer. 26he strength of our study lies in its unprecedented large sample size, focusing on LRPC, bolstering both reliability and statistical power.The even distribution among the various treatment groups, inclusion of patients with low C/DCS, and meticulous age-controlled analysis ensured robust comparability.Furthermore, this study encompassed a substantial representation of black patients (13%), offering valuable insights into the potential disparities.However, we must acknowledge the inherent limitations of our NCDB-based investigation, notably its retrospective and non-randomized nature, which may have introduced selection bias despite rigorous efforts to control for age and comorbidities, even with meticulous endeavors using propensity score analysis to balance different cohorts.It is also worth noting that the inability to distinguish between AS and WW in the NLT category owing to the nature of NCDB data limits our ability to assess the specific impact of each approach.While NLT in younger patients treated at academic institutions likely represents AS and most likely WW in those older than 75 years, determining the intention of NLT for patients between 70 and 74 years becomes more challenging due to the limited information available in the NCDB dataset.The Gleason scoring modification in 2005 led to risk group migration in some previously thought to be low Gleason scores upgraded to scores of 7 or higher. 30,31Given that our patient population spanned from 2004 to 2015, it is conceivable that some patients from before 2005 may have been classified as having Gleason 7 under the modified Gleason system, making it challenging to fully assess the implications of these changes in our study's conclusion.Furthermore, because of the inherent risk of sampling bias with prostate biopsy and the use of non-MRI-targeted biopsies, higher-risk prostate cancer with occult, synchronous, or metachronous, high-grade disease missed by biopsy could be included in the radiation groups or the NLT group, especially when the data are primarily from the pre-MRI era.Lastly, because of the nature of NCDB data, information regarding patients' symptoms, including urinary obstruction, previous sexual function, prostate volume, quality of life, and disease-specific mortality, may not be obtained, which could play a role in treatment decisions and outcomes.
Summary of patient characteristics of overall study population.Chi-squared test result of demographics and treatments before and after propensity score weighted adjustment.
T A B L E 1Abbreviations: EBRT, external-beam radiation therapy; NLT, no local treatment; PSI, prostate seed implant; RP, radical prostatectomy.*Level of income by zipcode.**Percentage of high school graduates by zipcode.T A B L E 2

Table 4
presents a comparison of the survival rates of the different treatment modalities relative to NLT across various age (0.89, p = 0.0020), and 9% (0.91, p = 0.0111) in patients aged <60, and 60-64, respectively.However, EBRT significantly improved survival in older patients by 6% (1.06, p = 0.0160) and 27% (1.27, p < 0.0001) in those aged 70-74 and over 75 years, respectively.Similarly, PSI did not improve survival in age groups younger than 64 years but exhibited significant survival benefits of 6% Abbreviations: A/RP, Academic/Research Program; AA, African American; CCCP, Comprehensive Community Cancer Program; CCP, Community Cancer Program; EBRT, external-beam radiation therapy; Gov, government; INCP, Integrated Network Cancer Program; NI, no insurance; NLT, no local treatment, RP, radical prostatectomy; PSI, prostate seed implant.T A B L E 2 (Continued) 74, and over 75, respectively.Thus, the survival advantages of EBRT and PSI increased with age, particularly in patients older than 70 years for EBRT and 65 years for PSI.In essence, NLT yielded non-inferior survival outcomes for younger patients compared with radiation modalities when surgery was not chosen.

3.5 | Survival by race and insurance
RP, EBRT, and PSI consistently demonstrated significant survival benefits across racial groups, mirroring trends in most demographics except for the uninsured or other racial groups (TableS4).EBRT and PSI predominantly benefited those with government insurance and lowerincome brackets but not those with private insurance or F I G U R E 2 Kaplan-Meier plot for overall survival probabilities based on treatment modalities.Abbreviations: EBRT, external-beam radiation therapy; NLT, no local treatment; PSI, prostate seed implant; RP, radical prostatectomy; S.E., standard error.T A B L E 3 Accelerated failure time model for overall survival rates among treatment groups compared to NLT.T A B L E 4 Accelerated failure time model results for each treatment stratified by age.